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New approaches to find novel antibiotics

The brightly coloured sponges, soft corals and sea squirts living on marine reefs are in a constant battle for survival, competing with each other for limited space to live and mature. These soft bodied marine animals are also under ever-present threat from predatory reef animals, such as sea slugs and fish, which they cannot move to avoid.
Their main weapons in this fight are potent chemicals.

For these animals, the chemicals serve as protection, but for us they are a rich source of biologically active molecules and a possible avenue in the search for new antibiotics to counter the rapid emergence of antibiotic resistance in bacteria.

Perhaps the most threatening antibiotic-resistant bacterium is methicillin-resistant Staphylococcus aureus, commonly referred to as MRSA or a “hospital bug”, which generally targets soft human tissues. The compromised ability to manage MRSA infection, particularly in immunocompromised patients, has resulted in numerous hospital-related deaths, a problem compounded by its spread into the general community. A report published in the Journal of the American Medical Association showed that, in 2007, more deaths in the United States were attributed to MRSA than to Aids.

To develop an antibiotic, scientists traditionally look for a biological mechanism that is specific to the bacterium, called a biological target, and then attempt to inhibit it using a drug. They achieve this by binding a drug to a biological molecule (such as a protein) in the bacterium, which stops it from functioning normally.

For example, penicillin antibiotics bind to proteins in the bacterium responsible for manufacturing cell walls. This means that the bacterium’s cells are not rigid and strong enough to protect it, and the bacterium dies. But importantly, penicillin does not affect humans, because we do not have the same enzyme. This is referred to as “drug specificity”.

Unfortunately, biological targets are particularly susceptible to natural selection pressures and this causes antibiotic resistance. Our research aims to find new methods of drug target selection to reduce the likelihood of resistance and to find naturally occurring chemicals in South Africa’s marine organisms to develop new drugs.

Antibiotic resistance occurs when the target protein mutates and this makes the antibiotic less able to bind with its target. This mutation will rapidly spread through a bacterial population, causing widespread antibiotic resistance.

Our project’s strategy to avoid this is to identify protein targets that mediate numerous interconnected biological pathways. We’re looking for the first domino in a long line of dominoes.

These proteins, known as “highly connected proteins”, are the beginning of a cascade of interlinked biological processes. If we interfere with these highly connected proteins, it causes a catastrophic collapse of this cascade and the bacterium dies.

Because of the large number of biological pathways that rely on highly connected proteins, these proteins are less prone to random mutations and this makes them ideal targets and less likely to cause antibiotic resistance.

But there is a glitch: highly connected proteins are common and occur in a wide variety of organisms. This means we lose the advantage of drug specificity, potentially leading to toxic side effects.

Our best candidate at the moment, identified by our colleagues at the University of British Columbia, is pyruvate kinase, a highly connected protein but also a potential non-specific biological target. Pyruvate kinase catalyses (facilitates) the formation of a molecule called pyruvate, which is a precursor to many biological building blocks, including fatty acids and certain amino acids.

Fortunately, there are small structural differences between human and MRSA pyruvate kinase. We have exploited these differences so that the antibiotic prefers to bind to MRSA pyruvate kinase rather than to human pyruvate kinase, even though it could possibly bind to both.

Natural compounds have traditionally been an excellent inspiration for pharmaceutical development. Because they cannot evade predators and have few physical defences, marine invertebrates, such as sponges, have evolved chemical defence mechanisms against enemies and other immobile species competing for space on the reefs.

These defensive chemicals are designed to interact with biological targets, and this has profound implications for modern medicine.

Our research group was invited by the University of British Columbia to submit marine natural products to test for possible MRSA pyruvate kinase inhibition, and of the 968 submissions from seven countries, only two natural products were found to inhibit MRSA pyruvate kinase. Both were from a sea sponge from the Aliwal Shoal in KwaZulu-Natal

Using computer modelling, we identified and synthesised a series of new molecules, inspired by the original natural products, and they were found to improve the MRSA pyruvate kinase inhibition activity, uncovering vital information for future drug design

But while we work on a way to thwart MRSA, these kind of bacteria are extremely resilient, meaning we will likely always be fighting against their mutations.

This work was conducted in collaboration between Rhodes University and the University of British Columbia. Clinton Veale is a PhD candidate at Rhodes University.

This publication is the culmination of a six-month-long Mail & Guardian project, called Science Voices, to teach postgraduate science students how to turn their academic writing into something the public can read and enjoy.